Gangliosides are cell surface glycosphingolipids containing one or more sialic acid residues. It has been suggested that gangliosides may be localized within detergent-resistant cell membrane microdomains termed “rafts”, which may provide the environment for some proteins to function by bringing together adapter molecules, modifiers, substrates, or cofactors that would be otherwise too distant or too dilute to form complexes and activate a signal cascade. However, little has been proposed regarding the possible mechanism of action of gangliosides in signal transduction.
Ganglioside GD2 is reportedly expressed at low levels in certain neuronal populations, but is highly prevalent in many types of tumors (neuroblastoma, melanoma, small cell carcinoma of the lung, gliomas, soft tissue sarcomas and B cell lymphoma).
The extracellular matrix component Tenascin-R was described recently as a natural ligand for GD2 (Probstmeier et al., 1999). However, relatively little is known about the biological function(s) of GD2 and the functional nature of its interaction with ligands such as Tenascin-R.
GD2 has been extensively studied as a tumor marker and is used clinically as a target for antibody-mediated therapy (e.g. anti-GD2 mAb 3F8) (Cheung et al., 1985). However, anti-GD2 mAb 3F8 applied therapeutically to patients causes acute and transient pain immediately after administration. Anti-GD2 mAb 3F8-based therapeutics have been suggested for use in a wide range of cancer therapeutics and diagnostics, including neuroblastoma and leptomeningeal cancer. For example, 131I-labeled anti-GD2 3F8 monoclonal antibody has been used in targeted radioimmunotherapy (dosed at 20 mCi/kg) in conjunction with immunotherapy with 400 mg/m2 unlabeled/unmodified 3F8. Similarly, granulocyte-macrophage colony-stimulating factor (GM-CSF) has been used in conjunction with anti-GD2 monoclonal antibody 3F8 in the treatment of patients with neuroblastoma.